Targeting genomic receptors in voided urine for confirmation of benign prostatic hyperplasia.

Objectives: The objective of this study is to validate a hypothesis that a non-invasive optical imaging assay targeting genomic VPAC receptors on malignant cells shed in voided urine will represent either benign prostatic hyperplasia (BPH) or prostatic cancer (PCa). Risk for BPH in men 50-70 years old is 50-70% and PCa is 17%. BPH and PCa can coexist in 20% of men with BPH. Most commonly practiced methods to diagnose BPH do not distinguish BPH from PCa. Patients or Materials and Methods: Males with BPH (N = 97, 60.8 ± 6.3 years, prostate-specific antigen 0.7 ± 0.4 ng/mL) and without oncologic disease (N = 35, 63.4 ± 5.8 years, prostate-specific antigen < 1.5 ng/mL) signed informed consent form and provided voided urine. Urine was cytocentrifuged, cells collected on glass slide, fixed, treated with VPAC specific fluorophore TP4303 (Kd 3.1 × 10-8M), washed, incubated with DAPI and observed using a fluorescence microscope. Cells with no VPAC did not fluoresce (BPH) and those with VPAC had red-orange fluorescence (PCa). Real-time polymerase chain reaction analyses for VPAC and NKX3.1 assay for cell origin were performed. Results: Eighty-seven subjects were negative for VPAC expression. Positive VPAC expression was noted in 10 subjects. Patient chart review for clinical data on these 10 VPAC positive subjects showed five had nephrolithiasis, three had renal cysts, one had prostatitis and one was being treated with finasteride. Real-time polymerase chain reaction analysis-VPAC expressions for 7 normal and 12 BPH subjects were 1.31 ± 1.26 and 0.94 ± 0.89, respectively (P = 0.46). NKX3.1 showed cells of prostate origin for finasteride-treated patient. Specificity for VPAC urine assay for excluding prostate cancer in this BPH cohort was 88.5%, positive predictive value 0.00% and negative predictive value 100%. Conclusion: VPAC assay may contribute extensively for BPH diagnosis and warrant continued investigation.

Use of TP4303 to identify prostate cancer cells in voided urine samples.

INTRODUCTION: Prostate cancer is the second most common malignancy in men worldwide. Genomic VPAC receptors are expressed on malignant prostate cancer cells and can be targeted and imaged optically by a peptide labeled fluorophore. The objective of our study was to assess the feasibility of detecting cancer of the prostate using a voided urine sample. MATERIALS AND METHODS: Patients ≥ 40 years old, with lower urinary tract symptoms and serum PSA > 4 ng/mL formed the study group. The first 50 mL of voided urine sample was collected and processed. The cells that were shed in the voided urine were fixed and stained with a peptide TP4303 and incubated. The slide was then stained with DAPI which binds with the DNA in the nucleus. All patients underwent a standard 12-core TRUS-guided prostate biopsy. RESULTS: A total of 318 patients were included in the study, of these 158 were histologically confirmed cancers. Voided urine samples were positive for VPAC receptors in 154 (97.46%) of these. The remaining 160 patients had no cancer on the HPR examination and none of these patients were positive for VPAC receptors. CONCLUSIONS: This study validates our belief that patients with prostate cancer shed malignant cells in the urine that can be identified by targeting the VPAC receptors. If these results are further validated by multicentric studies, then this could form the basis for indications for a preliminary prostate biopsy in patients with elevated serum PSA but normal digital examination or in patients needing a repeat biopsy.

Corrigendum to "Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostat Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial" [Eur. Eurol. 84(2) (2023) 156-163].

BACKGROUND: Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. OBJECTIVE: To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT. DESIGN, SETTING, AND PARTICIPANTS: High-risk localized prostate cancer patients (>50% of patients had Gleason 9-10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS). RESULTS AND LIMITATIONS: After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70-1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73-1.14), DM (HR = 0.84, 95% CI 0.73-1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74-1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm. CONCLUSIONS: After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers. PATIENT SUMMARY: No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Risk of Secondary Malignancies After Pelvic Radiation: A Population-based Analysis.

Background and objective: Radiation therapy has increasingly been used in the management of pelvic malignancies. However, the use of radiation continues to pose a risk of a secondary malignancy to its recipients. This study investigates the risk of secondary malignancy development following radiation for primary pelvic malignancies. Methods: A retrospective cohort review of the Surveillance, Epidemiology, and End Results database from 1975 to 2016 was performed. Primary pelvic malignancies were subdivided based on the receipt of radiation, and secondary malignancies were stratified as pelvic or nonpelvic to investigate the local effect of radiation. Key findings and limitations: A total of 2 102 192 patients were analyzed (1 189 108 with prostate, 315 026 with bladder, 88 809 with cervical, 249 535 with uterine, and 259 714 with rectal/anal cancer). The incidence rate (defined as cases per 1000 person years) of any secondary malignancies (including but not limited to secondary pelvic malignancies) was higher in radiation patients than in nonradiation patients (incidence rate ratio [IRR] 1.04, confidence interval [CI] 1.03-1.05), with significantly greater rates noted in radiation patients with prostate (IRR 1.22, CI 1.21-1.24), uterine (IRR 1.34), and cervical (IRR 1.80, CI 1.72-1.88) cancer. While the overall incidence rate of any secondary pelvic malignancy was lower in radiation patients (IRR 0.79, CI 0.78-0.81), a greater incidence was still noted in the same cohorts including radiation patients with prostate (IRR 1.42, CI 1.39-1.45), uterine (IRR 1.15, CI 1.08-1.21), and cervical (IRR 1.72, CI 1.59-1.86) cancer. Conclusions and clinical implications: Except for localized cervical cancer, when put in the context of median overall survival, the impact of radiation likely does not carry enough weight to change practice patterns. Radiation for pelvic malignancies increases the risk for several secondary malignancies, and more specifically, secondary pelvic malignancies, but with a relatively low absolute risk of secondary malignancies, the benefits of radiation warrant continued use for most pelvic malignancies. Practice changes should be considered for radiation utilization in malignancies with excellent cancer-specific survival such as cervical cancer. Patient summary: The use of radiation for the management of pelvic malignancies induces a risk of secondary malignancies to its recipients. However, the absolute risk being low, the benefits of radiation warrant its continued use, and a change in practice patterns is unlikely.

TARGET: A Randomized, Noninferiority Trial of a Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing.

PURPOSE: Germline genetic testing (GT) is important for prostate cancer (PCA) management, clinical trial eligibility, and hereditary cancer risk. However, GT is underutilized and there is a shortage of genetic counselors. To address these gaps, a patient-driven, pretest genetic education webtool was designed and studied compared with traditional genetic counseling (GC) to inform strategies for expanding access to genetic services. METHODS: Technology-enhanced acceleration of germline evaluation for therapy (TARGET) was a multicenter, noninferiority, randomized trial (ClinicalTrials.gov identifier: NCT04447703) comparing a nine-module patient-driven genetic education webtool versus pretest GC. Participants completed surveys measuring decisional conflict, satisfaction, and attitudes toward GT at baseline, after pretest education/counseling, and after GT result disclosure. The primary end point was noninferiority in reducing decisional conflict between webtool and GC using the validated Decisional Conflict Scale. Mixed-effects regression modeling was used to compare decisional conflict between groups. Participants opting for GT received a 51-gene panel, with results delivered to participants and their providers. RESULTS: The analytic data set includes primary outcome data from 315 participants (GC [n = 162] and webtool [n = 153]). Mean difference in decisional conflict score changes between groups was -0.04 (one-sided 95% CI, -∞ to 2.54; P = .01), suggesting the patient-driven webtool was noninferior to GC. Overall, 145 (89.5%) GC and 120 (78.4%) in the webtool arm underwent GT, with pathogenic variants in 15.8% (8.7% in PCA genes). Satisfaction did not differ significantly between arms; knowledge of cancer genetics was higher but attitudes toward GT were less favorable in the webtool arm. CONCLUSION: The results of the TARGET study support the use of patient-driven digital webtools for expanding access to pretest genetic education for PCA GT. Further studies to optimize patient experience and evaluate them in diverse patient populations are warranted.

External Validation of a Digital Pathology-based Multimodal Artificial Intelligence Architecture in the NRG/RTOG 9902 Phase 3 Trial.

BACKGROUND: Accurate risk stratification is critical to guide management decisions in localized prostate cancer (PCa). Previously, we had developed and validated a multimodal artificial intelligence (MMAI) model generated from digital histopathology and clinical features. Here, we externally validate this model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial. OBJECTIVE: To externally validate the MMAI model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial. DESIGN, SETTING, AND PARTICIPANTS: Our validation cohort included 318 localized high-risk PCa patients from NRG/RTOG 9902 with available histopathology (337 [85%] of the 397 patients enrolled into the trial had available slides, of which 19 [5.6%] failed due to poor image quality). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Two previously locked prognostic MMAI models were validated for their intended endpoint: distant metastasis (DM) and PCa-specific mortality (PCSM). Individual clinical factors and the number of National Comprehensive Cancer Network (NCCN) high-risk features served as comparators. Subdistribution hazard ratio (sHR) was reported per standard deviation increase of the score with corresponding 95% confidence interval (CI) using Fine-Gray or Cox proportional hazards models. RESULTS AND LIMITATIONS: The DM and PCSM MMAI algorithms were significantly and independently associated with the risk of DM (sHR [95% CI] = 2.33 [1.60-3.38], p < 0.001) and PCSM, respectively (sHR [95% CI] = 3.54 [2.38-5.28], p < 0.001) when compared against other prognostic clinical factors and NCCN high-risk features. The lower 75% of patients by DM MMAI had estimated 5- and 10-yr DM rates of 4% and 7%, and the highest quartile had average 5- and 10-yr DM rates of 19% and 32%, respectively (p < 0.001). Similar results were observed for the PCSM MMAI algorithm. CONCLUSIONS: We externally validated the prognostic ability of MMAI models previously developed among men with localized high-risk disease. MMAI prognostic models further risk stratify beyond the clinical and pathological variables for DM and PCSM in a population of men already at a high risk for disease progression. This study provides evidence for consistent validation of our deep learning MMAI models to improve prognostication and enable more informed decision-making for patient care. PATIENT SUMMARY: This paper presents a novel approach using images from pathology slides along with clinical variables to validate artificial intelligence (computer-generated) prognostic models. When implemented, clinicians can offer a more personalized and tailored prognostic discussion for men with localized prostate cancer.

Prostatectomia radical minimamente invasiva: transición de laparoscopia pura a laparoscopia asistida por robot / Minimally invasive radical prostatectomy: transition from pure laparoscopic to robotic-assisted radical prostatectomy

OBJETIVO: El abordaje laparoscópico asistido por robot en la prostatectomía radical es cada vez más utilizado y se ha convertido en una modalidad de tratamiento oncológico efectivo bien documentado. En este estudio, presentamos la experiencia inicial de un solo cirujano en una sola institución con prostatectomía laparoscópica asistida por robot (PRAR) estableciendo una comparación con su experiencia previa en la prostatectomía laparoscópica pura (PRL).MÉTODOS: Se trata de una revisión retrospectiva de los resultados quirúrgicos de un solo cirujano realizando la PRL y la transición a la PRAR. Las características básicas y los resultados obtenidos de doscientos setenta y cinco pacientes sometidos a PRR por un único y entrenado, urólogo oncológico, se analizaron y se compararon con 45 pacientes sometidos a prostatectomía radical laparoscópica por el mismo cirujano. Se evaluaron las características de los pacientes, de los tumores y de la técnica operatoria, así como los resultados funcionales. Se utilizaron cuestionarios validados, incluyendo el International Prostate Symptom Score (IPSS) y el Índice Internacional de Función Eréctil (IIEF), en la evaluación de los parámetros urinarios y sexuales(AU)

RESULTADOS: Las características preoperatorias de los pacientes y de los tumores incluidos (edad, PSA, índice de Gleason) fueron similares en ambos grupos, PRL y PRAR. El tiempo quirúrgico promedio (195 vs 299 minutos), la pérdida estimada de sangre (223 vs 299 ml), la necesidad de transfusión de sangre (1,5% vs 4,4%) y la estancia media (1,95 vs 2,63 días) se redujeron significativamente entre pacientes sometidos a PRAR en comparación con aquellos sometidos a prostatectomía radical laparoscópica. En cuanto a los resultados funcionales, la continencia a los 12 meses fue superior en los pacientes sometidos PRAR con respecto a la PRL (94% vs 82%). Entre aquellos sujetos potentes preoperatoriamente sometidos a procedimientos de preservación neurovascular bilateral, el 82% de los tratados con PRAR mantienen la potencia a los 24 meses en comparación con sólo el 62% de los sometidos a PRL.CONCLUSIONES: La combinación de ajustes en la técnica quirúrgica entre la PRLy la PRAR, junto con un compromiso institucional concurrentes a un exitoso programa de cirugía robótica, ha generado unos resultados funcionales, oncológicos y quirúrgicos superiores(AU)

OBJECTIVES: The robotic-assisted laparoscopic approach to radical prostatectomy is increasingly utilized and has become well documented as an effective oncologic treatment modality. In this study, we report the initial experience of a single surgeon at a single institution with robotic-assisted laparoscopic prostatectomy (RALP) drawing a comparison to his prior experience with pure laparoscopic prostatectomy (LRP).METHODS: This is a retrospective review of surgical results from a single surgeon performing LRP and transitioning to RALP. Baseline characteristics and outcomes of two hundred seventy five patients undergoing RALP by a single, fellowship-trained, urologic oncologist were analyzed and compared to 45 patients undergoing LRP by the same surgeon. Patient, tumor, and operative characteristics as well as functional outcomes were evaluated. Validated questionnaires, including the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF), were utilized in the assessment of urinary and sexual parameters. RESULTS: Preoperative patient and tumor characteristics (age, PSA, Gleason score) were similar in both the LRP and RALP groups. Mean operative time (195 vs. 299 minutes), estimated blood loss (223 vs. 299 mL), need for blood transfusion (1.5% vs. 4.4%) and mean length of stay (1.95 vs. 2.63 days) were significantly reduced among patients undergoing RALP as compared to those undergoing LRP. In terms of functional outcomes, continence at 12 months was better among patients undergoing RALP as compared to LRP (94% vs. 82%). In preoperatively potent men undergoing bilateral nerve sparing procedures, RALP conferred 82% potency at 24 months as opposed to only 62% following LRP.CONCLUSIONS: The combination of adjustment in surgical technique from LRP to RALP along with a concurrent institutional commitment to a successful robotic surgery program, has yielded superior operative, oncologic, and functional results(AU)